Polyglutamine androgen receptor-mediated neuromuscular disease.

An expanded polyglutamine (polyQ) tract at the amino-terminus of the androgen receptor (AR) confers toxic properties responsible for neuronal and non-neuronal degeneration in spinal and bulbar muscular atrophy (SBMA), one of nine polyQ expansion diseases. Both lower motor neurons and peripheral tissues, including skeletal muscle, are affected, supporting the notion that SBMA is not a pure motor neuron disease but a degenerative disorder of the neuromuscular system. Here, we review experimental evidence demonstrating both nerve and muscle degeneration in SBMA model systems and patients.

Defects in Neuromuscular Transmission May Underlie Motor Dysfunction in Spinal and Bulbar Muscular Atrophy.

Unlabelled: Spinal and bulbar muscular atrophy (SBMA) in men is an androgen-dependent neuromuscular disease caused by expanded CAG repeats in the androgen receptor (AR). Whether muscle or motor neuron dysfunction or both underlies motor impairment in SBMA is unknown. Muscles of SBMA mice show significant contractile dysfunction, implicating them as a likely source of motor dysfunction, but whether disease also impairs neuromuscular transmission is an open question.

RAN translation-What makes it run?

Nucleotide-repeat expansions underlie a heterogeneous group of neurodegenerative and neuromuscular disorders for which there are currently no effective therapies. Recently, it was discovered that such repetitive RNA motifs can support translation initiation in the absence of an AUG start codon across a wide variety of sequence contexts, and that the products of these atypical translation initiation events contribute to neuronal toxicity. This review examines what we currently know and do not know about repeat associated non-AUG (RAN) translation in the context of established canonical and non-canonical mechanisms of translation initiation.

Depression and clinical progression in spinocerebellar ataxias.

Background: Depression is a common comorbidity in spinocerebellar ataxias (SCAs) but its association with ataxia progression is not well understood.

Objectives: To study the prevalence and influence of depressive symptoms in SCAs.

Methods: We studied 300 participants with SCA 1, 2, 3 and 6 from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) and repeatedly measured depressive symptoms by the 9-item Patient Health Questionnaire (PHQ-9) along with other clinical features including ataxia, functional status, and quality of life every 6 months for 2 years.

Clinical-Genetic Associations in the Prospective Huntington at Risk Observational Study (PHAROS): Implications for Clinical Trials.

Importance: Identifying measures that are associated with the cytosine-adenine-guanine (CAG) expansion in individuals before diagnosis of Huntington disease (HD) has implications for designing clinical trials.

Objective: To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS).

Design, Setting, And Participants: A prospective, multicenter, longitudinal cohort study was conducted at 43 US and Canadian Huntington Study Group research sites from July 9, 1999, through December 17, 2009.

Androgen Receptor Gene Polymorphism, Aggression, and Reproduction in Tanzanian Foragers and Pastoralists.

The androgen receptor (AR) gene polymorphism in humans is linked to aggression and may also be linked to reproduction. Here we report associations between AR gene polymorphism and aggression and reproduction in two small-scale societies in northern Tanzania (Africa)--the Hadza (monogamous foragers) and the Datoga (polygynous pastoralists). We secured self-reports of aggression and assessed genetic polymorphism of the number of CAG repeats for the AR gene for 210 Hadza men and 229 Datoga men (aged 17-70 years).

Trial of short-course antimicrobial therapy for intraabdominal infection.

Background: The successful treatment of intraabdominal infection requires a combination of anatomical source control and antibiotics. The appropriate duration of antimicrobial therapy remains unclear.

Methods: We randomly assigned 518 patients with complicated intraabdominal infection and adequate source control to receive antibiotics until 2 days after the resolution of fever, leukocytosis, and ileus, with a maximum of 10 days of therapy (control group), or to receive a fixed course of antibiotics (experimental group) for 4±1 calendar days.

Reductions in behavioral deficits and neuropathology in the R6/2 mouse model of Huntington's disease following transplantation of bone-marrow-derived mesenchymal stem cells is dependent on passage number.

Introduction: Huntington's disease (HD) is an autosomal dominant disorder caused by an expanded CAG repeat (greater than 38) on the short arm of chromosome 4, resulting in loss and dysfunction of neurons in the neostriatum and cortex, leading to cognitive decline, motor dysfunction, and death, typically occurring 15 to 20 years after the onset of motor symptoms. Although an effective treatment for HD has remained elusive, current studies using transplants of bone-marrow-derived mesenchymal stem cells provides considerable promise. This study further investigates the efficacy of these transplants with a focus on comparing how passage number of these cells may affect subsequent efficacy following transplantation.

Biallelic mutations in huntington disease: A new case with just one affected parent, review of the literature and terminology.

Patients with biallelic mutations for Huntington disease (HD) are rare. We present a 46-year-old female with two expanded Huntingtin (HTT) alleles with just one known affected parent. This is the first reported patient with molecular studies performed to exclude HTT uniparental disomy (UPD).

Vascular risk factors and clinical progression in spinocerebellar ataxias.

Background: The contributions of vascular risk factors to spinocerebellar ataxia (SCA) are not known.

Methods: We studied 319 participants with SCA 1, 2, 3, and 6 and repeatedly measured clinical severity using the Scale for Assessment and Rating of Ataxia (SARA) for 2 years. Vascular risk factors were summarized by CHA2DS2-VASc scores as the vascular risk factor index.

Contractile dysfunction in muscle may underlie androgen-dependent motor dysfunction in spinal bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is characterized by progressive muscle weakness linked to a polyglutamine expansion in the androgen receptor (AR). Current evidence indicates that mutant AR causes SBMA by acting in muscle to perturb its function. However, information about how muscle function is impaired is scant.

Huntington disease: pathogenesis and treatment.

Huntington disease (HD) is an autosomal dominant inherited neurodegenerative disease characterized by progressive motor, behavioral, and cognitive decline, culminating in death. It is caused by an expanded CAG repeat in the huntingtin gene. Even years before symptoms become overt, mutation carriers show subtle but progressive striatal and cerebral white matter atrophy by volumetric MRI.

Human adipose-derived mesenchymal stem cells as a new model of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease is an X-linked CAG/polyglutamine expansion motoneuron disease, in which an elongated polyglutamine tract (polyQ) in the N-terminal androgen receptor (ARpolyQ) confers toxicity to this protein. Typical markers of SBMA disease are ARpolyQ intranuclear inclusions. These are generated after the ARpolyQ binds to its endogenous ligands, which promotes AR release from chaperones, activation and nuclear translocation, but also cell toxicity.

A knockin mouse model of spinocerebellar ataxia type 3 exhibits prominent aggregate pathology and aberrant splicing of the disease gene transcript.

Polyglutamine diseases, including spinocerebellar ataxia type 3 (SCA3), are caused by CAG repeat expansions that encode abnormally long glutamine repeats in the respective disease proteins. While the mechanisms underlying neurodegeneration remain uncertain, evidence supports a proteotoxic role for the mutant protein dictated in part by the specific genetic and protein context. To further define pathogenic mechanisms in SCA3, we generated a mouse model in which a CAG expansion of 82 repeats was inserted into the murine locus by homologous recombination.

A comparison of the short-term settling of three scleral lens designs.

Purpose: Scleral gas-permeable lenses are rapidly gaining international popularity. Unlike corneal gas-permeable lenses, scleral lenses are fitted to the bulbar conjunctiva and settle into the tissue after insertion. To date, we are unaware of any studies examining the settling behavior of three varying scleral lens designs.

Synergic prodegradative activity of Bicalutamide and trehalose on the mutant androgen receptor responsible for spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is an X-linked motoneuron disease due to a CAG triplet-repeat expansion in the androgen receptor (AR) gene, which is translated into an elongated polyglutamine (polyQ) tract in AR protein (ARpolyQ). ARpolyQ toxicity is activated by the AR ligand testosterone (or dihydrotestosterone), and the polyQ triggers ARpolyQ misfolding and aggregation in spinal cord motoneurons and muscle cells. In motoneurons, testosterone triggers nuclear toxicity by inducing AR nuclear translocation.

The role for alterations in neuronal activity in the pathogenesis of polyglutamine repeat disorders.

Polyglutamine diseases are a class of neurodegenerative diseases that share an expansion of a glutamine-encoding CAG tract in the respective disease genes as a central hallmark. In all of these diseases there is progressive degeneration in a select subset of neurons, and the mechanisms behind this degeneration remain unclear. Emerging evidence from animal models of disease has identified abnormalities in synaptic signaling and intrinsic excitability in affected neurons, which coincide with the onset of symptoms and precede apparent neuropathology.

Pathogenic mechanisms and therapeutic strategies in spinobulbar muscular atrophy.

We review the genetic and clinical features of spinobulbar muscular atrophy (SBMA), a progressive neuromuscular disorder caused by a CAG/glutamine tract expansion in the androgen receptor. SBMA was the first polyglutamine disease to be discovered, and we compare and contrast it with related degenerative disorders of the nervous system caused by expanded glutamine tracts. We review the cellular and animals models that have been most widely used to study this disorder, and highlight insights into disease pathogenesis derived from this work.

The Cag pathogenicity island and interaction between TLR2/NOD2 and NLRP3 regulate IL-1β production in Helicobacter pylori infected dendritic cells.

Helicobacter pylori colonization of the stomach affects about half of the world population and is associated with the development of gastritis, ulcers, and cancer. Polymorphisms in the IL1B gene are linked to an increased risk of H. pylori associated cancer, but the bacterial and host factors that regulate interleukin (IL)-1β production in response to H.

A polyglutamine expansion disease protein sequesters PTIP to attenuate DNA repair and increase genomic instability.

Glutamine (Q) expansion diseases are a family of degenerative disorders caused by the lengthening of CAG triplet repeats present in the coding sequences of seemingly unrelated genes whose mutant proteins drive pathogenesis. Despite all the molecular evidence for the genetic basis of these diseases, how mutant poly-Q proteins promote cell death and drive pathogenesis remains controversial. In this report, we show a specific interaction between the mutant androgen receptor (AR), a protein associated with spinal and bulbar muscular atrophy (SBMA), and the nuclear protein PTIP (Pax Transactivation-domain Interacting Protein), a protein with an unusually long Q-rich domain that functions in DNA repair.

Early cognitive dysfunction in the HD 51 CAG transgenic rat model of Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder in humans caused by an expansion of a CAG trinucleotide repeat that produces choreic movements, which are preceded by cognitive deficits. The HD transgenic rat (tgHD), which contains the human HD mutation with a 51 CAG repeat allele, exhibits motor deficits that begin when these rats are 12 months of age. However, there are no reports of cognitive dysfunction occurring prior to this.

Clinical profile, BRCA2 expression, and the androgen receptor CAG repeat region in Egyptian and Moroccan male breast cancer patients.

Introduction: Male breast cancer (MBC) is a rare disease. Rates of MBC in Northern Africa vary by region. The age-standardized incidence for MBC is higher in Morocco than in Egypt, and the Egyptian rate is similar to the U.

Toward understanding Machado-Joseph disease.

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is the most common inherited spinocerebellar ataxia and one of many polyglutamine neurodegenerative diseases. In MJD, a CAG repeat expansion encodes an abnormally long polyglutamine (polyQ) tract in the disease protein, ATXN3. Here we review MJD, focusing primarily on the function and dysfunction of ATXN3 and on advances toward potential therapies.